Neuropsychological development in children with early and continuously treated phenylketonuria : association with biochemical markers

PKU is a genetically inherited inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. The failure of this enzyme causes incomplete metabolism of protein ingested in the diet, specifically the conversion of one amino acid, phenylalanine, to tyrosine, which is a precursor to the neurotransmitter dopamine. Rising levels of phenylalanine is toxic to the developing brain, disrupting the formation of white matter tracts. The impact of tyrosine deficiency is not as well understood, but is hypothesized to lead to a low dopamine environment for the developing brain. Detection in the newborn period and continuous treatment (a low protein phe-restricted diet supplemented with phenylalanine-free protein formulas) has resulted in children with early and continuously treated PKU now developing normal I.Q. However, deficits in executive function (EF) are common, leading to a rate of Attention Deficit Hyperactivity Disorder (ADHD) up to five times the norm. EF worsens with exposure to higher phenylalanine levels, however recent research has demonstrated that a high phenylalanine to tyrosine ratio (phenylalanine:tyrosine ratio), which is hypothesised to lead to poorer dopamine function, has a more negative impact on EF than phenylalanine levels alone. Research and treatment of PKU is currently phenylalanine-focused, with little investigation of the impact of tyrosine on neuropsychological development. There is no current consensus as to the veracity of tyrosine monitoring or treatment in this population. Further, the research agenda in this population has demonstrated a primary focus on EF impairment alone, even though there may be additional neuropsychological skills compromised (e.g., mood, visuospatial deficits). The aim of this PhD research was to identify residual neuropsychological deficits in a cohort of children with early and continuously treated phenylketonuria, at two time points in development (early childhood and early adolescence), separated by eight years. In addition, this research sought to determine which biochemical markers were associated with neuropsychological impairments. A clinical practice survey was also undertaken to ascertain the current level of monitoring/treatment of tyrosine in this population. Thirteen children with early and continuously treated PKU were tested at mean age 5.9 years and again at mean age 13.95 years on several neuropsychological measures. Four children with hyperphenylalaninemia (a milder version of PKU) were also tested at both time points and provide a comparison group in analyses. Associations between neuropsychological function and biochemical markers were analysed. A between groups analysis in adolescence was also conducted (children with PKU compared to their siblings) on parent report measures of EF and mood. Minor EF impairments were evident in the PKU group by age 6 years and these persisted into adolescence. Life-long exposure to high phenylalanine:tyrosine ratio and/or low tyrosine independent of phenylalanine were significantly associated with EF impairments at both time points. Over half the children with PKU showed severe impairment on a visuospatial task, and this was associated only with concurrent levels of tyrosine in adolescence. Children with PKU also showed a statistically significant decline in a language comprehension task from 6 years to adolescence (going from normal to subnormal), this deficit was associated with lifetime levels of phenylalanine. In comparison, the four children with hyperphenylalaninemia demonstrated normal function at both time points, across all measures. No statistically significant differences were detected between children with PKU and their siblings on the parent report of EF and mood. However, depressive symptoms were significantly correlated with: EF; long term high phe:tyr exposure; and low tyrosine levels independent of phenylalanine. The practice survey of metabolic clinics from 12 countries indicated a high level of variability in terms of monitoring/treatment of tyrosine in this population. Whilst over 80% of clinics surveyed routinely monitored tyrosine levels in their child patients, 25% reported treatment strategies to increase tyrosine (and thereby lower the phenylalanine:tyrosine ratio) under a variety of patient presentation conditions. Overall, these studies have shown that EF impairments associated with PKU provide support for the dopamine-deficiency model. A language comprehension task showed a different trajectory, serving a timely reminder that non-EF functions also remain vulnerable in this population; and that normal function in childhood does not guarantee normal function by adolescence. Mood impairments were associated with EF impairments as well as long term measures of phenylalanine:tyrosine and/or tyrosine. The implications of this research for enhanced clinical guidelines are discussed given varied current practice.

The Biodex Isokinetic Dynamometer for knee strength assessment in children : advantages and limitations

Objective: To critically appraise the Biodex System 4 isokinetic dynamometer for strength assessment of children. Methods: Appraisal was based on experiences from two independent laboratories involving testing of 213 children. Issues were recorded and the manufacturer was consulted regarding appropriate solutions. Results: The dynamometer had insufficient height adjustment for alignment of the knee for some children, requiring the construction of padding to better fit the child within the dynamometer. Potential for entrapment of the non-testing leg was evident in the passive and eccentric modes and a leg bracket restraint was constructed. Automated gravity correction did not operate when protocols were linked or data was exported to an external device. Conclusions: Limitations were noted, some of which were applicable to knee strength testing in general and others which were specific to use with children. However, most of these obstacles could be overcome, making the Biodex System 4 suitable for assessment of knee strength in children.

Symbolic number : the integration of magnitude and spatial representations in children aged 6 to 8 years

The process of learning symbolic Arabic digits in early childhood requires that magnitude and spatial information integrates with the concept of symbolic digits. Previous research has separately investigated the development of automatic access to magnitude and spatial information from symbolic digits. However, developmental trajectories of symbolic number knowledge cannot be fully understood when considering components in isolation. In view of this, we have synthesized the existing lines of research and tested the use of both magnitude and spatial information with the same sample of British children in Years 1, 2 and 3 (6-8 years of age). The physical judgment task of the numerical Stroop paradigm (NSP) demonstrated that automatic access to magnitude was present from Year 1 and the distance effect signaled that a refined processing of numerical information had developed. Additionally, a parity judgment task showed that the onset of the Spatial-Numerical Association of Response Codes (SNARC) effect occurs in Year 2. These findings uncover the developmental timeline of how magnitude and spatial representations integrate with symbolic number knowledge during early learning of Arabic digits and resolve inconsistencies between previous developmental and experimental research lines.

Representational change and strategy use in children's number line estimation during the first years of primary school

Background: The objective of this study was to scrutinize number line estimation behaviors displayed by children in mathematics classrooms during the first three years of schooling. We extend existing research by not only mapping potential logarithmic-linear shifts but also provide a new perspective by studying in detail the estimation strategies of individual target digits within a number range familiar to children. Methods: Typically developing children (n = 67) from Years 1 – 3 completed a number-to-position numerical estimation task (0-20 number line). Estimation behaviors were first analyzed via logarithmic and linear regression modeling. Subsequently, using an analysis of variance we compared the estimation accuracy of each digit, thus identifying target digits that were estimated with the assistance of arithmetic strategy. Results: Our results further confirm a developmental logarithmic-linear shift when utilizing regression modeling; however, uniquely we have identified that children employ variable strategies when completing numerical estimation, with levels of strategy advancing with development. Conclusion: In terms of the existing cognitive research, this strategy factor highlights the limitations of any regression modeling approach, or alternatively, it could underpin the developmental time course of the logarithmic-linear shift. Future studies need to systematically investigate this relationship and also consider the implications for educational practice.

The assessment of mental health in children with intellectual disability

Aim: Individuals with intellectual disability (ID) have higher rates of mental health problems than the general population. Assessment tends to rely heavily on self-report, but persons with ID often have difficulties in identifying and describing their own thoughts and feelings. Measures that are psychometrically sound with typically developing populations may not be as robust in samples with ID. The aim of the current study was to examine a range of self-report measures for assessing the mental health of children with ID, and to consider the appropriateness of minor modifications to those instruments. Method: The participants were 58 children with ID (mean 11.7 years) attending Year 6 in mainstream primary schools. At the first time point they completed four established measures of depression, anxiety and mood. Minor modifications were made to wording and format at re-administration six months later. Results: Internal consistency varied considerably across measures. Modifications resulted in small or no improvements, but the results were relatively consistent over time and across similar measures. Some gender differences were evident. Conclusions: The findings confirm the difficulties that children with ID may have when responding to self-report measures of mental health, and suggest that care should be taken in choice of instruments. While modifications can produce small improvements, it is clear that more robust measures of mental health are needed for persons with ID.

Child characteristics associated with delay of gratification in children with Down syndrome

Aim: Children with Down syndrome have been identified as having difficulty delaying gratification when compared to mental age matched children who are developing typically. This study investigated the association between individual characteristics hypopthesized to be associated with ability to delay as well as the strategies children used in a waiting task. Method: Thirty-two children with Down syndrome and 50 typically developing children matched for mental age completed the tasks. Observations of their behaviour while waiting were video-recorded for later analysis. In addition, parents completed questionnaires with respect to their child’s personality and behaviour. Results: Children with Down syndrome were significantly less able to delay gratification than the comparison group. Different patterns of association were found for the two groups between the observational and questionnaire measures and delay time. Conclusions: Children with Down syndrome have greater difficulty delaying gratification than would be predicted on the basis of their mental age. The contributions to delay appear to differ from those for typically developing children and these differences need to be considered when planning interventions for developing this skill

Antibiotics overuse in children with upper respiratory tract infections in Saudi Arabia : risk factors and potential interventions

Background: Antibiotics misuse is currently one of the major public health issues worldwide. This misuse can lead to the development of bacterial resistance, increasing the burden of chronic diseases, rising costs of health services, and the development of side effects. Several factors may influence this pattern of overuse. Objectives:This article will review the pertinent factors contributing to the overuse of antibiotics worldwide, and to assess the intervention strategies to limit this overuse. Methods: studies about antibiotics use in children were reviewed from several electronic databases, such as MEDLINE and Pubmed. Results: Factors contributing to the overuse of antibiotics could include psychosocial factors, such as behaviors and attitudes (e.g. self-medication, over-the-counter medication, or patients/parents pressure), and demographic factors, such as socio-economic status and education level. Several intervention strategies were reported to be effective in reducing the overuse of antibiotics, such as health education, doctor-patient communication, and policies change. Multifaceted interventions were found to be the most effective in reducing the antibiotics overuse.

Refraction in children : a comparison of two methods of accommodation control

Purpose: The prevalence of refractive errors in children has been extensively researched. Comparisons between studies can, however, be compromised because of differences between accommodation control methods and techniques used for measuring refractive error. The aim of this study was to compare spherical refractive error results obtained at baseline and using two different accommodation control methods – extended optical fogging and cycloplegia, for two measurement techniques – autorefraction and retinoscopy. Methods: Participants comprised twenty-five school children aged between 6 and 13 years (mean age: 9.52 ± 2.06 years). The refractive error of one eye was measured at baseline and again under two different accommodation control conditions: extended optical fogging (+2.00DS for 20 minutes) and cycloplegia (1% cyclopentolate). Autorefraction and retinoscopy were both used to measure most plus spherical power for each condition. Results: A significant interaction was demonstrated between measurement technique and accommodation control method (p = 0.036), with significant differences in spherical power evident between accommodation control methods for each of the measurement techniques (p < 0.005). For retinoscopy, refractive errors were significantly more positive for cycloplegia compared to optical fogging, which were in turn significantly more positive than baseline, while for autorefraction, there were significant differences between cycloplegia and extended optical fogging and between cycloplegia and baseline only. Conclusions: Determination of refractive error under cycloplegia elicits more plus than using extended optical fogging as a method to relax accommodation. These findings support the use of cycloplegic refraction compared with extended optical fogging as a means of controlling accommodation for population based refractive error studies in children.

Assessing the overuse of antibiotics in children with URTIs in Saudi Arabia : development of the parental perception on antibiotics scale (PAPA scale)

Background: Antibiotic overuse is influenced by several factors that can only be measured using a valid and reliable psychosocial measurement instrument. This study aims to establish translation and early stage validation of an instrument recently developed by this research team to measure factors influencing the overuse of antibiotics in children with upper respiratory tract infections in Saudi Arabia. Method: The content evaluation panel was composed of area experts approached using the Delphi Technique. Experts were provided with the questionnaires iteratively, on a three-round basis until consensus on the relevance of items was reached independently. Translation was achieved by adapting Brislin’s model of translation. Results: After going through the iterative process with the experts, consensus was reached to 58 items (including demographics). Experts also pointed out some issues related to ambiguity and redundancy in some items. A final Arabic version was produced from the translation process. Conclusion: This study produced preliminary validation of the developed instrument from the experts’ contributions. Then, the instrument was translated from English to Arabic. The instrument will undergo further validation steps in the future, such as construct validity.

Assessing the overuse of antibiotics in children in Saudi Arabia : validation of the parental perception on antibiotics scale (PAPA scale)

Background Antibiotics overuse is a global public health issue influenced by several factors, of which some are parent-related psychosocial factors that can only be measured using valid and reliable psychosocial measurement instruments. The PAPA scale was developed to measure these factors and the content validity of this instrument was assessed. Aim This study further validated the recently developed instrument in terms of (1) face validity and (2) construct validity including: deciding the number and nature of factors, and item selection. Methods Questionnaires were self-administered to parents of children between the ages of 0 and 12 years old. Parents were conveniently recruited from schools’ parental meetings in the Eastern Province, Saudi Arabia. Face validity was assessed with regards to questionnaire clarity and unambiguity. Construct validity and item selection processes were conducted using Exploratory factor analysis. Results Parallel analysis and Exploratory factor analysis using principal axis factoring produced six factors in the developed instrument: knowledge and beliefs, behaviours, sources of information, adherence, awareness about antibiotics resistance, and parents’ perception regarding doctors’ prescribing behaviours. Reliability was assessed (Cronbach’s alpha = 0.78) which demonstrates the instrument as being reliable. Conclusion The ‘factors’ produced in this study coincide with the constructs contextually identified in the development phase of other instruments used to study antibiotic use. However, no other study considering perceptions of antibiotic use had gone beyond content validation of such instruments. This study is the first to constructively validate the factors underlying perceptions regarding antibiotic use in any population and in parents in particular.

Teachers’ knowledge of anxiety and identification of excessive anxiety in children

This study examined primary school teachers’ knowledge of anxiety and excessive anxiety symptoms in children. Three hundred and fifteen primary school teachers completed a questionnaire exploring their definitions of anxiety and the indications they associated with excessive anxiety in primary school children. Results showed that teachers had an understanding of what anxiety was in general but did not consistently distinguish normal anxiety from excessive anxiety, often defining all anxiety as a negative experience. Teachers were able to identify symptoms of excessive anxiety in children by recognizing anxiety-specific and general problem indications. The results provided preliminary evidence that teachers’ knowledge of anxiety and anxiety disorders does not appear to be a barrier in preventing children’s referrals for mental health treatment. Implications for practice and directions for future research are discussed.